Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the s-enantiomer and methods of use

ABSTRACT

Ketogenic compositions including a non-racemic mixture of beta-hydroxybutyrate (BHB) enriched with the S-enantiomer are formulated to control ketone body levels in a subject. The non-racemic mixture of BHB is enriched with the S-enantiomer to modulate the effect of ketone bodies in the subject and control the rate at which ketosis is achieved. In some aspects a composition for controlling ketone body level in a subject contains a dietetically or pharmaceutically acceptable carrier and a non-racemic mixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate, wherein the non-racemic mixture contains from about 52% to 99% by enantiomeric equivalents of S-beta-hydroxybutyrate enantiomer and from about 48% to about 1% by enantiomeric equivalents of R-beta-hydroxybutyrate enantiomer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a division of U.S. patent application Ser. No.15/936,849, filed Mar. 27, 2018, which claims the benefit of U.S.Provisional Patent Application No. 62/607,578, filed Dec. 19, 2017, thedisclosures of which are incorporated herein by reference in theirentirety.

BACKGROUND 1. Field of the Invention

Disclosed herein are non-racemic beta-hydroxybutyrate compounds, salts,esters, and compositions enriched with the S-enantiomer ofbeta-hydroxybutyrate and methods for controlling and/or modulating bloodlevels and/or the effects of ketone bodies in a subject.

2. Related Technology

In periods of fasting, extreme exercise, and/or low carbohydrateconsumption, glucose and glycogen stores in the body are rapidly usedand can become quickly depleted. Failure to replenish glucose stores asthey become depleted causes the body to metabolically shift to thecreation and use of ketone bodies for energy (“ketosis”). Ketone bodiescan be used by cells of the body as a fuel to satisfy the body's energyneeds, including the brain and heart. During prolonged fasting, forexample, blood ketone levels can increase to 2-3 mmol/L or more. It isconventionally understood that when blood ketones rise above 0.5 mmol/L,the heart, brain and peripheral tissues are using ketone bodies (e.g.,beta-hydroxybutyrate and acetoacetate) as the primary fuel source. Thiscondition is referred to as ketosis. Between 1.0 mmol/L and 3.0 mmol/Lthe condition is called “nutritional ketosis.”

Upon transitioning into ketosis, or in other words, during ketogenicmetabolism in the liver, the body uses dietary and bodily fats as aprimary energy source. Consequently, once in ketosis, one can induceloss of body fat by controlling dietary fat intake and maintaining lowcarbohydrate intake and blood level to sustain ketosis.

While in ketosis, the body is in ketogenisis and essentially burning fatfor its primary fuel. The body cleaves fats into fatty acids andglycerol and transforms fatty acids into acetyl CoA molecules, which arethen eventually transformed through ketogenisis into the water solubleketone bodies beta-hydroxybutyrate (“β-hydroxybutyrate” or “BHB”),acetoacetate (also known as acetylacetonate), and acetone in the liver.Beta-hydroxybutyrate and acetoacetate are the ketone bodies used by thebody for energy while acetone is removed and expelled as a by-product ofketogenesis.

The metabolism of ketone bodies is associated with several beneficialeffects, including anticonvulsant effects, enhanced brain metabolism,neuroprotection, muscle sparing properties, and improved cognitive andphysical performance. Science-based improvements in efficiency ofcellular metabolism, managed through ketone supplementation, can havebeneficial impacts on physical, cognitive health, and psychologicalhealth, and a long-term impact on health with respect to commonavoidable diseases such as obesity, cardiovascular disease,neurodegenerative diseases, diabetes, and cancer.

Despite the many health advantages of pursuing a ketogenic diet orlifestyle and maintaining a state of nutritional ketosis, there remainsignificant barriers to pursuing and maintaining a ketogenic state. Oneof these barriers is the difficulty of transitioning into a ketogenicstate. The fastest endogenous way to entering ketosis through depletingglucose stores in the body is by fasting combined with exercise. This isphysically and emotionally demanding and is extremely challenging evenfor the most motivated and disciplined.

Additionally, the transition into ketosis is often accompanied byhypoglycemia, which can cause lethargy and light-headedness in many,resulting in an uncomfortable physiological and mental state commonlyreferred to as the “low-carb flu.” In addition, many people experience adown regulation in their metabolism as the body naturally goes into an“energy-saving” mode. Some suggest that these transitory symptoms maylast as long as two to three weeks. During this transition period, if asubject consumes a meal or snack containing carbohydrates above therestrictive amount, there is an immediate termination of ketogenisis,exiting the body from its state of ketosis, as the body shifts back toglucose utilization for its primary fuel and the transition into ketosismust begin anew.

If a subject is successful in establishing ketosis, the act ofsustaining ketosis is likewise difficult, if not more difficult, due tothe need to maintain a rigid dietary ratio of carbohydrates and proteinto fats. It is further complicated by the disruption of normalelectrolyte balances that often occurs when transitioning into andmaintaining a ketogenic state. The depletion and lowering of glycogenstores in the liver and muscles lessens the ability of the body toretain water, leading to more frequent urination, and accordingly, agreater loss of electrolytes. Further, the drop in insulin levels causedby ketosis effects the rate at which certain electrolytes are extractedby the kidneys, additionally lowering electrolyte levels in the body.Negative effects of electrolyte imbalance include muscle aches, spasms,twitches and weakness, restlessness, anxiety, frequent headaches,feeling very thirsty, insomnia, fever, heart palpitations or irregularheartbeats, digestive issues such as cramps, constipation or diarrhea,confusion and trouble concentrating, bone disorders, joint pain, bloodpressure changes, changes in appetite or body weight, fatigue (includingchronic fatigue syndrome), numbness in joints, and dizziness, especiallywhen standing up suddenly.

Some compositions used to promote ketosis in a mammal include a racemicmixture of beta-hydroxybutyrate (RS-beta-hydroxybutyrate orDL-beta-hydroxybutyrate). Other compositions, such as those disclosed inU.S. Patent Publication No. 2017/0296501 to Lowery et al., contain onlythe endogenous form of beta-hydroxybutyrate, or R-beta-hydroxybutyrate,and none of the non-endogenous enantiomer, or S-beta-hydroxybutyrate.Others, such as those disclosed in U.S. Pat. No. 8,642,654 to Clarke etal., consist mostly or entirely of a single beta-hydroxybutyrate ester(3R)-hydroxybutyl (3R)-hydroxybutyrate. Other enantiomers, such as(3R)-hydroxybutyl (3 S)-hydroxybutyrate, (3 S)-hydroxybutyl(3R)-hydroxybutyrate, and (3 S)-hydroxybutyl (3 S)-hydroxybutyrate, aremostly or entirely omitted. The omission of enantiomers that are not theendogenous form of beta-hydroxybutyrate is based on the view thatS-beta-hydroxybutyrate (aka (3 S)-hydroxybutyrate) is ineffective oreven harmful.

BRIEF SUMMARY

Disclosed herein are compositions and methods for controlling ketonebody levels in a subject, including promoting and/or sustaining ketosisin a subject over an extended period of time. Example compositionsinclude a non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate, wherein the non-racemic mixture contains from52% to 99% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer and 48% to 1% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

The non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate contains more of the S-beta-hydroxybutyrateenantiomer than the endogenous form (R-enantiomer) produced by a mammalin order to provide a more controlled and sustained ketogenic effectcompared to a racemic mixture and/or compositions enriched with theR-enantiomer. Because the R-beta-hydroxybutyrate enantiomer isendogenously produced by a mammal during ketosis, administering theR-beta-hydroxybutyrate enantiomer to a subject provides a quantity thatcan be immediately utilized by the body, such as for producing energy(e.g., as an alternative energy source to glucose). However, this effectis modulated and extended when the S-enantiomer is the predominantcomponent.

Contrary to compositions that are deliberately enriched with theR-enantiomer or that minimize or eliminate S-beta-hydroxybutyratealtogether, the non-racemic mixture is enriched with theS-beta-hydroxybutyrate enantiomer, which is not endogenously produced bya mammal, in order to produce one or more desired effects in the mammal,as discussed herein.

In some embodiments, the compositions disclosed herein can be used in amethod for increasing ketone body level in a subject, includingpromoting and/or sustaining ketosis in a subject, comprisingadministering to a subject in need thereof a nutritionally orpharmaceutically effective amount of one or more compositions disclosedherein. Examples of beneficial effects of increased ketone body level ina subject include one or more of appetite suppression, weight loss, fatloss, reduced blood glucose level, improved mental alertness, increasedphysical energy, improved cognitive function, reduction in traumaticbrain injury, reduction in effect of diabetes, improvement ofneurological disorder, reduction of cancer, reduction of inflammation,anti-aging, antiglycation, reduction in epileptic seizer, improved mood,increased strength, increased muscle mass, or improved body composition.

In some embodiments, administering the non-racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate in the enantiomericratios or percentages disclosed herein provide one or more of: increasedendogenous production of R-beta-hydroxybutyrate and acetoacetate;endogenous conversion of the S-beta-hydroxybutyrate into one or both ofR-beta-hydroxybutyrate and acetoacetate; endogenous conversion of theS-beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis;metabolism of the S-beta-hydroxybutyrate independent of conversion toR-beta-hydroxybutyrate and/or acetoacetate; increased fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling by the S-beta-hydroxybutyrate that modulatesmetabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity;and production of acetyl-CoA.

In some embodiments, the composition may include a carrier and up to100% of S-beta-hydroxybutyrate enantiomer and no R-beta-hydroxybutyrateenantiomer.

Additional features and advantages will be set forth in part in thedescription that follows, and in part will be obvious from thedescription, or may be learned by practice of the embodiments disclosedherein. It is to be understood that both the foregoing brief summary andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments disclosed herein or asclaimed.

DETAILED DESCRIPTION I. Definitions

As used herein “beta-hydroxybutyrate,” also known as β-hydroxybutyrate,βHB or BHB, means a compound having the general formula CH₃CH₂OHCH₂COOHand the following chemical structure:

where,

X can be hydrogen, metal ion, amino cation, such as from an amino acid,alkanyl, alkenyl, or aryl.

Whether beta-hydroxybutyrate is the S- or R-enantiomer depends on thetetrahedral orientation of the hydroxy (or oxy group in the case of anester) on the 3-carbon (beta-carbon) in relationship to the planarcarboxyl group.

Beta-hydroxybutyrate, typically R-beta-hydroxybutyrate, which is theendogenous form, can be utilized by a patient's body as a fuel sourceduring instances of low glucose levels in the subject or when apatient's body is supplemented with a usable form ofbeta-hydroxybutyrate. Beta-hydroxybutyrate is commonly referred to as a“ketone body.”

As used herein, a “ketogenic composition” is formulated to increaseketone body level in a subject, including inducing and/or sustaining astate of elevated ketone bodies at a desired level, such as ketosis, ina subject to which it is administered.

As used herein, “subject” or “patient” refers to members of the animalkingdom, including mammals, such as but not limited to, humans and otherprimates; rodents, fish, reptiles, and birds. The subject may be anyanimal requiring therapy, treatment, or prophylaxis, or any animalsuspected of requiring therapy, treatment, or prophylaxis. Prophylaxismeans that regiment is undertaken to prevent a possible occurrence, suchas where a high glucose or diabetes is identified. “Patient” and“subject” are used interchangeably herein.

“Ketosis” as used herein refers to a subject having blood ketone levelswithin the range of about 0.5 mmol/L and about 16 mmol/L in a subject.Ketosis may improve mitochondrial function, decrease reactive oxygenspecies production, reduce inflammation and increase the activity ofneurotrophic factors. “Keto-adaptation” as used herein refers toprolonged nutritional ketosis (>1 week) to achieve a sustainednonpathological “mild ketosis” or “therapeutic ketosis.”

In some cases, “elevated ketone body level” may not mean that a subjectis in a state of “clinical ketosis” but nevertheless has an elevatedsupply of ketones for producing energy and/or for carrying out otherbeneficial effects of ketone bodies. For example, a subject that is“ketone adapted” may not necessarily have elevated blood serum levels ofketone bodies but rather is able to utilize available ketone bodies morerapidly compared to a subject that is not “ketone adapted.” In suchcase, “elevated ketone body level” can refer to the total quantityand/or rate of ketone bodies being utilized by the subject rather thanblood plasma levels per se.

The term “medium chain triglycerides” (MCT) refers to molecules having aglycerol backbone attached to three medium chain fatty acids. Mediumchain fatty acids can range from 6 to 12 carbon atoms in length, andmore likely 8 to 10 carbon atoms in length. Exemplary fatty acids arecaprylic acid, also known as octanoic acid, comprising 8 carbonmolecules, and capric acid, also known as decanoic acid, comprising 10carbon molecules. MCTs, medium chain fatty acids, and mono- anddi-glycerides are ketone body precursors that can provide an additionalsource for the production of ketone bodies independent ofbeta-hydroxybutyrate.

The term “administration” or “administering” is used herein to describethe process in which the disclosed compositions are delivered to asubject. The composition may be administered in various ways includingoral, intragastric, and parenteral (referring to intravenous andintra-arterial and other appropriate parenteral routes), among others.

II. Non-Racemic Beta-Hydroxybutyrate Compositions

Compositions for increasing ketone body level in a subject, includingcontrolling and/or modulating ketosis, comprise a non-racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate, wherein thenon-racemic mixture contains from 52% to 99% by enantiomeric equivalentsof the S-beta-hydroxybutyrate enantiomer and 48% to 1% by enantiomericequivalents of the R-beta-hydroxybutyrate enantiomer.

In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrateand S-beta-hydroxybutyrate contains from 53% to 98%, 55% to 96%, 57% to93%, 60% to 90%, or 65% to 85% by enantiomeric equivalents of theS-beta-hydroxybutyrate enantiomer and 47% to 2%, 45% to 4%, 3% to 7%,40% to 10%, or 35% to 15%, by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

The non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate contains more of the S-beta-hydroxybutyrateenantiomer rather than the endogenous form produced by a mammal, whichis the R-beta-hydroxybutyrate enantiomer, in order to provide for morecontrolled, gradual, extended, and/or modulated ketogenic effectcompared to either a racemic mixture or composition enriched with theR-beta-hydroxybutyrate enantiomer. Because the R-beta-hydroxybutyrateenantiomer is endogenously produced by a mammal during ketosis,administering the R-beta-hydroxybutyrate enantiomer to a subjectprovides an additional quantity and/or increased blood plasma level thatcan be immediately utilized by the body, such as for producing energy(e.g., as an alternative energy source to glucose). However, this effectis modulated and extended due to the S-enantiomer being the predominantcomponent.

Contrary to compositions that deliberately minimize or eliminateS-beta-hydroxybutyrate, the non-racemic mixture contains a majorityquantity of the S-beta-hydroxybutyrate enantiomer, which is notendogenously produced by a mammal, in order to produce one or moredesired effects in the mammal. For example, administeringS-beta-hydroxybutyrate along with R-beta-hydroxybutyrate can result inat least one of: (1) increased endogenous production ofR-beta-hydroxybutyrate and acetoacetate; (2) endogenous conversion ofthe S-beta-hydroxybutyrate into one or both of R-beta-hydroxybutyrateand acetoacetate; (3) endogenous conversion of theS-beta-hydroxybutyrate into fatty acids and sterols; (4) prolongedketosis; (5) metabolism of the S-beta-hydroxybutyrate independent ofconversion to R-beta-hydroxybutyrate and/or acetoacetate; (6) increasedfetal development; (7) increased growth years; (8) reduced endogenousproduction of acetone during ketosis; (9) signaling by theS-beta-hydroxybutyrate that modulates metabolism ofR-beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11)production of acetyl-CoA.

The non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate can be used, for example, to produce one or moredesired effects in the subject, including but not limited to, appetitesuppression, weight loss, fat loss, reduced blood glucose level,improved mental alertness, increased physical energy, improved cognitivefunction, reduction in traumatic brain injury, reduction in effect ofdiabetes, improvement of neurological disorder, reduction of cancer,reduction of inflammation, anti-aging, antiglycation, reduction inepileptic seizer, improved mood, increased strength, increased musclemass, or improved body composition.

In some embodiments, the composition may include a carrier and up to100% of S-beta-hydroxybutyrate enantiomer and no R-beta-hydroxybutyrateenantiomer.

The S-beta-hydroxybutyrate and R-beta-hydroxybutyrate can be provided invarious forms, such as salts and esters. The percent of enantiomerequivalents of each of the S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is defined by the molar quantity of eitherS-beta-hydroxybutyrate or R-beta-hydroxybutyrate divided by the totalmolar quantity of both S-beta-hydroxybutyrate andR-beta-hydroxybutyrate. The amounts of any cations forming salts and/oralcohols forming esters are excluded and do not count in determining thepercent of enantiomeric equivalents of each of S-beta-hydroxybutyrateand R-beta-hydroxybutyrate.

In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrateand S-beta-hydroxybutyrate is provided in a composition that includes adietetically or pharmaceutically acceptable carrier. Examples includepowders, liquids, tablets, capsules, food products, food additives,beverages, beverage additives, candies, suckers, pastilles, foodsupplements, sprays, injectables, and suppositories.

In some embodiments, the non-racemic mixture of S-beta-hydroxybutyrateand R-beta-hydroxybutyrate can be provided as a salt, such as one ormore salts of alkali metals, alkaline earth metals, transition metals,amino acids, or metabolites of amino acids. Examples include lithiumsalts, sodium salts, potassium salts, magnesium salts, calcium salts,zinc salts, iron salts (as iron II and/or iron III), chromium salts,manganese salts, cobalt salts, copper salts, molybdenum salts, seleniumsalts, arginine salts, lysine salts, leucine salts, isoleucine salts,histidine salts, ornithine salts, citrulline salts, glutamine salts, andcreatine salts.

In some embodiments, the non-racemic mixture of S-beta-hydroxybutyrateand R-beta-hydroxybutyrate can be provided as one or more esters, suchas mono-, di-, tri-, oligo-, and polyesters. Examples include mono-esterof ethanol, mono-ester of 1-propanol, mono-ester of 1,2-propanediol,di-ester of 1,2-propanediol, mono-ester of 1,3-propanediol, di-ester of1,3-propanediol, mono-ester of S—, R—, or S—R-1,3-butanediol, di-esterof S—, R—, or S—R-1,3-butanediol, mono-ester of glycerin, (3S)-hydroxybutyl (3 S)-hydroxybutyrate mono-ester, (3R)-hydroxybutyl (3S)-hydroxybutyrate, mono-ester, di-ester of glycerin, tri-ester ofglycerin, ester of acetoacetate, dimers, trimers, oligomers, andpolyesters containing repeating units of beta-hydroxybutyrate, andcomplex oligomers or polymers of beta-hydroxybutyrate and one or moreother hydroxy-carboxylic acids, such as lactic acid, citric acid,acetoacetic acid, quinic acid, shikimic acid, salicylic acid, tartaricacid, and malic acid, and/or beta-hydroxybutyrate and or one or morediols, such as 1,3-propanediol and 1,3-butanediol, and one or morepolyacids, such as tartaric acid, citric acid, malic acid, succinicacid, and fumaric acid. While (3R)-hydroxybutyl (3R)-hydroxybutyratemono-ester can be included, it should not cause the amount ofR-hydroxybutyrate to exceed 48% by enantiomeric equivalents.

In some embodiments, the composition may further include at least onemedium chain fatty acid, or a mono-, di- or triglyceride of the at leastone medium chain fatty acid, wherein the medium chain fatty acid hasfrom 6 to 12 carbons, preferably from 8 to 10 carbons. Although lesspreferred, the composition may comprise at least one short chain fattyacid, or a mono-, di- or triglyceride of the at least one short chainfatty acid, having less than 6 carbons and/or at least one long chainfatty acid, or a mono-, di- or triglyceride of the at least one longchain fatty acid, having more than 12 carbons.

Examples and sources of the medium chain fatty acid, or an ester thereofsuch as a medium chain triglyceride, include coconut oil, coconut milkpowder, fractionated coconut oil, palm oil, palm kernel oil, caprylicacid, capric acid, isolated medium chain fatty acids, such as isolatedhexanoic acid, isolated octanoic acid, isolated decanoic acid, mediumchain triglycerides either purified or in natural form such as coconutoil, and ester derivatives of the medium chain fatty acids ethoxylatedtriglyceride, enone triglyceride derivatives, aldehyde triglyceridederivatives, monoglyceride derivatives, diglyceride derivatives, andtriglyceride derivatives, and salts of the medium chain triglycerides.Ester derivatives optionally include alkyl ester derivatives, such asmethyl, ethyl, propyl, butyl, hexyl, etc.

The administration of a non-racemic mixture of S-beta-hydroxybutyrateand R-beta-hydroxybutyrate results in controlled, prolonged, andmodulated blood levels of ketone bodies, thereby exploiting themetabolic and physiological advantages of sustained ketosis. Raising thelevels of ketone bodies in the blood provides a subject with greaterflexibility in diet options as compared to methods that aim to induceand sustain ketosis based on diet alone (e.g., based on fasting and/orlimited carbohydrate intake). For example, a subject that has beenadministered an appropriate amount of a non-racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate will be able to eat anoccasional carbohydrate or sugar-based food without jeopardizing theketogenic state and shifting back into a glucose-based metabolic state.Further, such administration facilitates easier transitioning into aketogenic state while reducing or eliminating the detrimental effectstypically associated with entering ketosis.

In some embodiments, a ketogenic composition additionally includes atherapeutically effective amount of vitamin D₃. Vitamin D₃ is believedto work in conjunction with magnesium and calcium to promote good bonehealth and to prevent undesirable calcification of soft tissues. Inpreferred embodiments, vitamin D₃ is included in an amount such that anaverage daily dose of the ketogenic composition includes about 200 IU(“International Units”) to about 8000 IU, or about 400 IU to about 4000IU, or about 600 IU to about 3000 IU of vitamin D₃. In some embodiments,vitamin D₃ is included in an amount such that an average daily dose ofthe ketogenic composition includes about 5 μg to about 200 μg, or about10 μg to about 100 μg, or about 15 μg to about 75 μg of vitamin D₃.

Some embodiments also include one or more additional ketone precursorsor supplements. These additional ketone precursors or supplements mightinclude acetoacetate, ketone esters, and/or other compounds that cause arise in blood ketone levels without adding more electrolytes to thebloodstream. Other additives include metabolites that enhance the effector transport of ketone bodies into mitochondria, caffeine, theobromine,and nootropics, such as L-alpha glycerylphosphorylcholine (“alpha GPC”).

The composition may include flavoring agents that help mask theotherwise poor taste of beta-hydroxybutyrate compounds. These includeessential oils, such as peppermint, natural and artificial sweeteners,and other flavorants known in the art.

In some embodiments, ketogenic compositions may further includes one ormore additional components configured to lower the hygroscopicity of thecomposition. For example, various anticaking agents, flow agents, and/ormoisture absorbers, in types and amounts that are safe for consumption,may be included. Such additional components may include one or more ofan aluminosilicate, ferrocyanide, carbonate or bicarbonate salt,silicate (e.g., sodium or calcium silicate), phosphate salt (e.g.,tricalcium phosphate), talcum, powdered cellulose, and the like.

III. Administration

In some embodiments, the compositions disclosed herein can be used in amethod for increasing ketone body level, including promoting and/orsustaining ketosis, in a subject comprising administering to a subjectin need thereof a nutritionally or pharmaceutically effective amount ofone or more compositions disclosed herein. Examples of beneficialeffects of increasing ketone body level, including promoting and/orsustaining ketosis, in a subject include one or more of appetitesuppression, weight loss, fat loss, reduced blood glucose level,improved mental alertness, increased physical energy, improved cognitivefunction, reduction in traumatic brain injury, reduction in effect ofdiabetes, improvement of neurological disorder, reduction of cancer,reduction of inflammation, anti-aging, antiglycation, reduction inepileptic seizer, improved mood, increased strength, increased musclemass, or improved body composition.

In some embodiments, administering the non-racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate in the enantiomericratios or percentages disclosed herein provide one or more of increasedendogenous production of R-beta-hydroxybutyrate and acetoacetate;endogenous conversion of the S-beta-hydroxybutyrate into one or both ofR-beta-hydroxybutyrate and acetoacetate; endogenous conversion of theS-beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis;metabolism of the S-beta-hydroxybutyrate independent of conversion toR-beta-hydroxybutyrate and/or acetoacetate; increased fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling by the S-beta-hydroxybutyrate that modulatesmetabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity;and production of acetyl-CoA.

Ketogenic compositions described herein may be administered to a subjectin therapeutically effective dosages and/or in frequencies to induce orsustain ketosis. In some embodiments, a single dose will include anamount of non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate ranging from about 0.5 gram to about 25 grams, orabout 0.75 gram to about 20 grams, or about 1 gram to about 15 grams, orabout 1.5 grams to about 12 grams.

In some embodiments, the ketogenic compositions can include or beadministered together with other supplements, such as vitamin D₃,vitamins, minerals, and others known in the art.

In some embodiments, the compositions may further include one or moremedium chain fatty acids, fatty acid esters, or mono-, di- ortriglycerides of medium chain fatty acids in order to provide anadditional source of ketone bodies, as discussed herein, for sustainingketosis for a longer period of time compared to if just the non-racemicmixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate is used byitself. In some embodiments, the composition is preferably administeredsuch that the ratio of the non-racemic mixture of S-beta-hydroxybutyrateand R-beta-hydroxybutyrate to medium chain fatty acid (or ester thereof)ranges from about 4:1 to about 1:4, or from about 2:1 to about 1:2, orfrom about 1.5:1 to about 1:1.5. Short chain fatty acids, esters, andglycerides thereof, though less preferred, can be used in addition to orinstead of medium chain fatty acids, fatty acid esters, or glyceridesthereof.

In some embodiments, the subject preferably follows a ketogenic dietthat restricts intake of carbohydrates and protein during the period ofadministration of the composition. In one example embodiment, thesubject may restrict the dietary intake to a ratio of about 65% fat,about 25% protein, and about 10% carbohydrates. The resultingtherapeutic ketosis provides a rapid and sustained keto-adaptation as ametabolic therapy for a wide range of metabolic disorders, and providesnutritional support for therapeutic fasting, weight loss, andperformance enhancement. As such, the composition is typicallyadministered once per day, twice per day, or three times per day to asubject desiring to promote and/or sustain a state of ketosis.

In a preferred embodiment, ketogenic compositions can be administeredvia oral administration in solid and/or powdered form, such as in apowdered mixture (e.g., powder filled gelatin capsules), hard-pressedtablets, or other oral administration route known to those skilled inthe art.

In some embodiments, multiple doses of the composition are administeredover a period of time. The frequency of administration of thecomposition can vary depending on any of a variety of factors, such astiming of treatment from previous treatments, objectives of thetreatment, and the like. The duration of administration of thecomposition (e.g., the period of time over which the agent isadministered), can vary depending on any of a variety of factors,including subject response, desired effect of treatment, etc.

The amount of the composition to be administered can vary according tofactors such as the degree of susceptibility of the individual, the age,sex, and weight of the individual, idiosyncratic responses of theindividual, and the like. The “therapeutically effective amount” is thatamount necessary to promote a therapeutically effective result in vivo(i.e., therapeutic ketosis). In accordance with the present disclosure,a suitable single dose size is a dose that is capable of preventing oralleviating (reducing or eliminating) a symptom in a patient whenadministered one or more times over a suitable time period.

The amount of composition administered will depend on potency,absorption, distribution, metabolism, and excretion rates of unusedketone bodies, electrolytes, the method of administration, and theparticular disorder being treated, as well as other factors known tothose of skill in the art. The dose should be sufficient to affect adesirable response, such as a therapeutic or prophylactic responseagainst a particular disorder or condition, taking into account theseverity of the condition to be alleviated. The compounds may beadministered once, or may be divided and administered over intervals oftime. It is to be understood that administration may be adjustedaccording to individual need and professional judgment of a personadministrating or supervising the administration of the compositions.

IV. Examples

The following is a description of exemplary non-racemic mixtures ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate compositions and otherketogenic compositions useful for raising ketone levels in a subject,including inducing and/or modulating a ketogenic state in a subject towhich they are administered. It should be appreciated that thebeta-hydroxybutyrate compounds described in the examples can be in theform of salts, esters, dimers, trimers, oligomers, and polymers, asdiscussed herein. The important thing from the standpoint of theexamples is the enantiomeric percentages or ratios ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate. In some cases, thecompositions can be a blend of salts and esters to provide a desiredelectrolyte balance and/or modulation of ketosis. The compositions canalso be combined with medium chain fatty acids, esters, glycerides, andother supplements as disclosed herein to provide a desired level ofelevated ketone bodies and other effects.

Example 1

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 52% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and48% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture. On theother hand, including the S-beta-hydroxybutyrate enantiomer provides fora longer state of ketosis and/or other benefits as disclosed herein.

The non-racemic mixture is readily administered as a ketogeniccomposition, such as in powder form as a dietary supplement mixed withfood or drink, in the form of one or more capsules or tablets, or inliquid form such as a mouth spray.

Example 2

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 53% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and47% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture or thenon-racemic mixture of Example 1. On the other hand, including theS-beta-hydroxybutyrate enantiomer provides for a longer state of ketosisand/or other benefits as disclosed herein, as compared to a compositionenriched with the R-beta-hydroxybutyrate enantiomer.

Example 3

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 55% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and45% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture or thenon-racemic mixtures of Examples 1 and 2. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition enriched with the R-beta-hydroxybutyrate enantiomer.

Example 4

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 57% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and43% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture or thenon-racemic mixtures of Examples 1-3. On the other hand, including theS-beta-hydroxybutyrate enantiomer provides for a longer state of ketosisand/or other benefits as disclosed herein, as compared to a compositionenriched with the R-beta-hydroxybutyrate enantiomer.

Example 5

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 60% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and40% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture or thenon-racemic mixtures of Examples 1-4. On the other hand, including theS-beta-hydroxybutyrate enantiomer provides for a longer state of ketosisand/or other benefits as disclosed herein, as compared to a compositionenriched with the R-beta-hydroxybutyrate enantiomer.

Example 6

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 65% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and35% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture or thenon-racemic mixtures of Examples 1-5. On the other hand, including theS-beta-hydroxybutyrate enantiomer provides for a longer state of ketosisand/or other benefits as disclosed herein, as compared to a compositionenriched with the R-beta-hydroxybutyrate enantiomer.

Example 7

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 70% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and30% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture or thenon-racemic mixtures of Examples 1-6. On the other hand, including theS-beta-hydroxybutyrate enantiomer provides for a longer state of ketosisand/or other benefits as disclosed herein, as compared to a compositionenriched with the R-beta-hydroxybutyrate enantiomer.

Example 8

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 75% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and25% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture or thenon-racemic mixtures of Examples 1-7. On the other hand, including theS-beta-hydroxybutyrate enantiomer provides for a longer state of ketosisand/or other benefits as disclosed herein, as compared to a compositionenriched with the R-beta-hydroxybutyrate enantiomer.

Example 9

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide 85% byenantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer and15% by enantiomeric equivalents of the R-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes less of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed for agiven dosage as compared to the same dosage of racemic mixture or thenon-racemic mixtures of Examples 1-6. On the other hand, including theS-beta-hydroxybutyrate enantiomer provides for a longer state of ketosisand/or other benefits as disclosed herein, as compared to a compositionenriched with the R-beta-hydroxybutyrate enantiomer.

Example 10

A non-racemic mixture of S-beta-hydroxybutyrate andR-beta-hydroxybutyrate is prepared by mixing one or moreS-beta-hydroxybutyrate compounds with a racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate to provide from 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by enantiomericequivalents of the S-beta-hydroxybutyrate enantiomer and 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, or 1% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer. Because the non-racemic mixtureincludes substantially less of the R-beta-hydroxybutyrate enantiomer,the onset of ketosis is significantly delayed for a given dosage ascompared to the same dosage of racemic mixture or the non-racemicmixtures of Examples 1-9. On the other hand, including theS-beta-hydroxybutyrate enantiomer provides for a longer state of ketosisand/or other benefits as disclosed herein.

Example 11

A composition comprising one or more S-beta-hydroxybutyrate compounds ismixed with a carrier to form a composition with 100% equivalents ofS-beta-hydroxybutyrate enantiomer and 0% equivalents ofR-beta-hydroxybutyrate enantiomer. Because the composition contains noR-beta-hydroxybutyrate enantiomer, the onset of ketosis is significantlydelayed for a given dosage as compared to the same dosage of racemicmixture or the non-racemic mixtures of Examples 1-10. On the other hand,including the S-beta-hydroxybutyrate enantiomer provides for a delayedand/or longer state of ketosis and/or other benefits as disclosedherein.

Example 12

Any of the foregoing examples is modified by combining the non-racemicmixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate with adietetically or pharmaceutically acceptable carrier.

Example 13

Any of the foregoing examples is modified by combining the non-racemicmixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate with one ormore medium chain triglycerides and/or one or more medium chain fattyacids and/or one or more mono- or diglycerides medium chain fatty acids.

Example 14

Any of the foregoing examples is modified by combining the non-racemicmixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate with one ormore supplements, such as vitamin D₃, vitamins, minerals, and othersknown in the art.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

1. A method of administering a ketone body composition to a subject inneed thereof, the ketone body composition comprising:S-beta-hydroxybutyrate or a non-racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate, wherein thecomposition comprises from 52% to 100% by enantiomeric equivalents ofthe S-beta-hydroxybutyrate and 48% to 0% by enantiomeric equivalents ofthe R-beta-hydroxybutyrate.
 2. The method of claim 1, wherein thenon-racemic mixture contains from 53% to 98% by enantiomeric equivalentsof the S-beta-hydroxybutyrate and 47% to 2% by enantiomeric equivalentsof the R-beta-hydroxybutyrate.
 3. The method of claim 1, wherein thenon-racemic mixture contains from 55% to 96% by enantiomeric equivalentsof the S-beta-hydroxybutyrate and 45% to 4% by enantiomeric equivalentsof the R-beta-hydroxybutyrate.
 4. The method of claim 1, wherein thenon-racemic mixture contains from 57% to 93% by enantiomeric equivalentsof the S-beta-hydroxybutyrate and 43% to 7% by enantiomeric equivalentsof the R-beta-hydroxybutyrate.
 5. The method of claim 1, wherein thenon-racemic mixture contains from 60% to 90% by enantiomeric equivalentsof the S-beta-hydroxybutyrate and 40% to 10% by enantiomeric equivalentsof the R-beta-hydroxybutyrate.
 6. The method of claim 1, wherein thenon-racemic mixture contains from 65% to 85% by enantiomeric equivalentsof the S-beta-hydroxybutyrate and 35% to 15% by enantiomeric equivalentsof the R-beta-hydroxybutyrate.
 7. The method of claim 1, wherein thecomposition comprises one or more salts of S-beta-hydroxybutyrate. 8.The method of claim 7, wherein the one or more salts ofS-beta-hydroxybutyrate comprise at least one of a sodium salt, potassiumsalt, magnesium salt, calcium salt, transition metal salt, or amino acidsalt of S-beta-hydroxybutyrate.
 9. The method of claim 8, wherein theamino acid salt of S-beta-hydroxybutyrate includes at least one aminoacid or amino acid metabolite selected from arginine, lysine, leucine,iso-leucine, histidine, ornithine, citrulline, glutamine, or creatine.10. The method of claim 1, wherein the non-racemic mixture contains atleast one S-beta-hydroxybutyrate ester.
 11. The method of claim 10,wherein the S-beta-hydroxybutyrate ester is a di-ester of a diol andS-beta-hydroxybutyrate.
 12. The method of claim 10, wherein theS-beta-hydroxybutyrate ester comprises at least one of mono-ester ofethanol, mono-ester of 1-propanol, mono-ester of 1,3-propanediol,di-ester of 1,3-propanediol, mono- or di-ester of S-1,3-butanediol,mono- or di-ester of R-1,3-butanediol, mono- or di-ester ofS—R-1,3-butanediol, or mono-, di-, or tri-ester of glycerin.
 13. Themethod of claim 1, wherein the composition further comprises a carrier,and wherein the carrier comprises a powder, a liquid, a tablet, acapsule, a food product, a food additive, a beverage, a beverageadditive, a food supplement a spray, an injectable, a suppository, apastille, a sucker, or a candy.
 14. The method of claim 1, furthercomprising vitamin D₃, such as in an amount of about 5 μg to about 200μg, or about 10 μg to about 100 μg, or about 15 μg to about 75 μg, or inan amount of about 200 IU to about 8000 IU, or about 400 IU to about4000 IU, or about 600 IU to about 3000 IU.
 15. The method of claim 1,wherein the composition further comprises at least one medium chainfatty acid, or a mono-, di- or triglyceride of the at least one mediumchain fatty acid.
 16. The method of claim 15, wherein the at least onemedium chain fatty acid has from 6 to 12 carbons, or from 8 to 10carbons.
 17. The method of claim 1, wherein the composition furthercomprises at least one of (i) a short chain fatty acid, or a mono-, di-or triglyceride of the at least one short chain fatty acid, having lessthan 6 carbons or (ii) a long chain fatty acid, or a mono-, di- ortriglyceride of the at least one long chain fatty acid, having more than12 carbons.
 18. The method of claim 1, wherein administration of thecomposition results in one or more of appetite suppression, weight loss,fat loss, reduced blood glucose level, improved mental alertness,increased physical energy, improved cognitive function, reduction intraumatic brain injury, reduction in effect of diabetes, improvement ofneurological disorder, reduction of cancer, reduction of inflammation,anti-aging, antiglycation, reduction in epileptic seizer, improved mood,increased strength, increased muscle mass, or improved body composition.19. The method of claim 1, wherein administration of the compositionresults in at least one of: increased endogenous production ofR-beta-hydroxybutyrate and acetoacetate; endogenous conversion of theS-beta-hydroxybutyrate into one or both of R-beta-hydroxybutyrate andacetoacetate; endogenous conversion of the S-beta-hydroxybutyrate intofatty acids and sterols; prolonged ketosis; metabolism of theS-beta-hydroxybutyrate independent of conversion toR-beta-hydroxybutyrate and/or acetoacetate; increased fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling by the S-beta-hydroxybutyrate that modulatesmetabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity;production of acetyl-CoA.
 20. A method of administering a nutritionallyor pharmaceutically effective amount of a ketone body composition to asubject in need thereof, the composition comprising:S-beta-hydroxybutyrate or a non-racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate, wherein thecomposition comprises from 52% to 100% by enantiomeric equivalents ofthe S-beta-hydroxybutyrate and 48% to 0% by enantiomeric equivalents ofthe R-beta-hydroxybutyrate.
 21. A method of administering anutritionally or pharmaceutically effective amount of a ketone bodycomposition to a subject in need thereof, the composition comprising: anutritionally or pharmaceutically acceptable carrier; andS-beta-hydroxybutyrate or a non-racemic mixture ofS-beta-hydroxybutyrate and R-beta-hydroxybutyrate, wherein thecomposition comprises from 52% to 100% by enantiomeric equivalents ofthe S-beta-hydroxybutyrate and 48% to 0% by enantiomeric equivalents ofthe R-beta-hydroxybutyrate.